We have used neuroimaging to explore the effects in the brain of allelic variation in the catechol-O-methyltransferase gene (COMT), which has been identified as a gene of interest for schizophrenia. It is well-established that, particularly in prefrontal cortex, COMT is prime determinant of dopamine catabolism, thereby influencing intrasynaptic dopamine levels. A common polymorphism in the COMT gene (val158met) leads to significantly reduced catabolic activity in the COMT enzyme moiety coded for by the methionine allele, with increased availability of dopamine in the prefrontal cortex (PFC). The valine allele has been associated with poor working memory and inefficient cortical processing, consistent with previous findings in animal that dopamine as being critical to determine the ratio of task-related to task-unrelated neural firing or tuning of PFC neurons. Postmortem studies have shown a direct correlation between valine-encoding alleles and increased dopamine synthesis in the midbrain, which suggested that this functional single nucleotide polymorphism (SNP) can modulate the interaction between the PFC and the midbrain. Building upon these findings, our group engaged in a study to demonstrate the specific interactions between PFC and midbrain dopamine synthesis in normal healthy living people as a function of COMT genotype. We used positron emission tomography (PET) to measure both regional cerebral blood flow (rCBF) during working memory and F-18 Fluoro-dopa uptake (to measure dopamine synthesis and presynaptic stores) in the same individuals. We not only demonstrated that valine carriers have increased midbrain FDOPA uptake, confirming in living persons the findings in postmortem brain specimens, we also extended our knowledge of the implications of this gene-related alteration by demonstrating that the COMT genotype determines the direction of the relationship between midbrain FDOPA and prefrontal rCBF during working memory. This work substantiates the idea of strong interactions between PFC and dopamine and of genetic control of the PFC-midbrain tuning mechanism and provides for the first time important corroborative evidence in humans that supports current concepts about dopaminergic modulation of PFC function and its effect on subcortical dopamine regulation. These data also explain a neurogenetic mechanism that underlies individual variation in the function of the prefrontal-midbrain network. Previous studies have also demonstrated that dopamine neurotransmission is dependent upon the val158met functional mutation in COMT in conjunction with a functional mutation in the variable number of tandem repeats in the dopamine transporter (DAT1) gene. Currently, we are investigating the effect of COMT val158met and DAT1 functional mutations on specific components of the reward system in healthy subjects. [unreadable] [unreadable] This year, we further examined how the dopamine system, which plays a crucial role in reward processing, affects aging individuals. Very little is known about the neurofunctional consequences of this age-related dopamine decline. In animals, a substantial body of data indicates that dopamine activity in the midbrain is tightly associated with reward processing. However, in humans there has been no direct demonstration of a link between midbrain dopamine and reward-related neural response. In this study, we directly characterize the interactions between midbrain dopamine function and the reward system in both healthy young and older subjects and identify changes in this regulatory circuit in healthy aging. Our multimodal approach, using both FDOPA PET and event-related 3T functional magnetic resonance imaging (fMRI) in the same subjects directly demonstrates a link between midbrain dopamine synthesis and reward-related prefrontal activity in humans. This shows that healthy aging induces functional alterations in the reward system, and identify an age-related change in the direction of the relationship between dopamine midbrain dopamine synthesis and prefrontal activity. These results indicate an age-dependent dopaminergic tuning mechanism for cortical reward processing and provide systems-level information about alteration of a key neural circuit in healthy aging. Important considerations when performing fMRI studies in aging: 1) normal aging can affect the cerebrovascular system, which affects the neurovascular coupling that is the basis of the BOLD fMRI signal; 2) older adults sometimes respond to cognitive activation paradigms with a smaller dynamic range of BOLD signal as compared to young; 3) the overall shape of the BOLD response does not change with age, but there may be a lag in the time-to-peak; and 4) there is a potential confound that brain volume is affected by aging which may impact PET data. Taken together, our data provide characterization of the interactions between midbrain dopamine function and the reward system in healthy aging; and identifies changes in this regulatory circuit across the adult lifespan. These results may prompt additional studies in the identified circuit and may lead to studies of mechanistically targeted therapeutic interventions involving the dopamine system in individuals, unlike our cohort, for whom the neural aging process has not been successful. [unreadable] [unreadable] Last year, we evaluated hormone effects on the reward circuit. We scanned the brain activity of women and men while they performed a task involving simulated slot machines. The women were scanned before and after ovulation. The fMRI data showed that the reward system responded differently when women anticipated a reward compared with when the reward was actually delivered, depending upon their menstrual phase. When they hit the jackpot and actually won a reward, women in the pre-ovulatory phase activated the striatum and circuit areas linked to pleasure and reward more than when in the post-ovulatory phase. The study also confirmed that the reward-related brain activity was directly linked to levels of sex hormones. Activity in the amygdala and hippocampus was consistent with estrogen levels regardless of cycle phase; activity in these areas was also triggered by progesterone levels while women were anticipating rewards during the post-ovulatory phase. Activity patterns that emerged when rewards were delivered during the post-ovulatory phase suggested that the effect of estrogen on the reward circuit might be altered by the presence of progesterone during that period. Men showed a different activation profile than women during both anticipation and delivery of rewards. For example, men had more activity in the striatum area during anticipation compared to women and women had more activity in the frontal cortex area at the time of reward delivery compared to men. While they were anticipating winning money, brain activity in the orbitofrontal cortex, part of the reward system thought to regulate emotion and reward-related planning behavior, was increased during women's pre-ovulatory (follicular) phase compared to post-ovulatory (luteal) phase. This was the first study of how sex hormones influence reward-evoked brain activity in humans, and provided insights into menstrual-related mood disorders, women's higher rates of mood and anxiety disorders, and their later onset and less severe course in schizophrenia. This study also shed light on the neural mechanism that renders women more vulnerable to addictive drugs during the pre-ovulation phase of the cycle.